Amiodarone HCl (2-butyl-3-benzofuranyl) [4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone hydrochloride, is a class III antiarrhythmic agent that possesses electro physiologic characteristics of all four Vaughan Williams classes. The hydrochloride salt is currently marketed in ampoules suitable for intravenous administration following dilution in dextrose (CORDARONE® IV, Wyeth-Ayerst). Each milliliter of a CORDARONE® ampoule contains 50 mg amiodarone HCl, 20.2 mg benzyl alcohol, 100 mg polysorbate 80, and water for injection. The pH of the commercial product after dilution in dextrose is approximately 3.8-4.0.
One inconvenience of the prior art product is a required step of admixing 1-6 ampoules in dextrose prior to administration. Since amiodarone can be used under emergency conditions to rapidly stabilize a patient's acute ventricular arrhythmia, this dilution step consumes valuable time. Other drawbacks of the admixing step include the possibility of dosage error, needle sticks, and/or solution contamination.
Another drawback of the prior art product is that the diluted formulations have a limited shelf life at room temperature. Generally, due to diminished sterility precautions brought about by opening the sterile container of the concentrate, the resulting diluted formulations must be used within 24 hours of dilution or be discarded. Obviously, such discarded quantities of the product increase costs for healthcare providers.
An additional drawback is that the diluted formulations have been shown to be incompatible with certain polymeric materials due to drug adsorption. This phenomenon creates dosing problems for health care providers, or requires the use of special material containers for dilution and delivery.
The product configuration and amiodarone formulations described in the present invention overcome these disadvantages. The ready-to-use premixed product configuration prevents loss of time spent diluting the concentrate, avoids potential problems of contamination, helps reduce use of sharp needles, decreases medical waste production, and eliminates dosage errors. Such benefits are due to the fact that medical personnel will be able to simply use a prepared container of the inventive composition off the shelf, as needed, without additional preparation. Moreover, the new premixed amiodarone formulations have an enhanced shelf life and an improved compatibility with polymeric container materials.
U.S. Pat. No. 6,143,778 issued Nov. 7, 2000, to Gautier et al. discloses an amiodarone composition concentrate for parenteral delivery after dilution. The disclosed composition requires a physiologically acceptable buffer solution capable of solubilizing the active principle and of maintaining the pH of the concentrated composition between 2.4 and 3.8 (Gautier et al., column 4, lines 8-54). Gautier et al. disclose an amiodarone hydrochloride formulation “which is at the same time concentrated, stable and dilutable.” (See column 1, lines 28-31, column 3, lines 34-39, and lines 47-56). Gautier et al., therefore, focus on the stability and admixing of the concentrate. The invention of this application provides a premixed amiodarone hydrochloride formulation which does not require dilution and does not utilize a buffer, not even for solubilizing the active, before parenteral administration to a patient.
Discussion regarding diluted amiodarone concentrations (i.e., admixtures) are set forth by Gautier et al., but no information is provided discussing the long-term stability (1 year or more) of the diluted product (column 5, lines 32-51). In the examples of a diluted form of the amiodarone, Gautier et al. teach pH levels of around 4 (see examples 2, 4, and 6 of Table, column 6, lines 45-53). Gautier et al. fail to appreciate the importance of a limited pH range of from about 2.9 to about 3.2, and preferably a pH of about 3.1 for long term stability and container compatibility of a diluted premix formulation. By focusing on the stability of a concentrate which is capable of dilution for immediate use or discard, Gautier et al. ignore the potential long term stability problems of the diluted product. That is, outside of the very narrow pH range, problems with drug degradation, particle formation, impurity formation, and container incompatibility can result. By addressing and solving these problems, the premix formulation of the present invention differs from Gautier et al.'s disclosure of both a concentrate and a diluted admix product.
Similarly, U.S. Pat. No. 5,234,949 issued Aug. 10, 1993, to Ehrenpreis et al., teaches a parenteral solution of amiodarone in acetate buffer. Ehrenpreis et al. disclose a preferred pH in the range of 3.5 to 3.8 (column 3, lines 53-54). This approach is contrary to the claimed composition and methods of the present invention.